Adolescence and emerging adulthood represent an important developmental period during which substance use, misuse, and abuse occur concomitantly with important changes in neurocognitive development, mental health, and the social environment, with consequences for adult adjustment. Existing literature linking the effects of youth substance use to adult adjustment demonstrates the importance of these factors, but is largely correlational and cross-sectional, and leaves equivocal their causal role. Poor adult adjustment may be the result of youth substance misuse, including possible neurotoxic effects on brain development during this sensitive period. However, factors present prior to substance use initiation, such as genetic liability, pre- existing brain anomalies reflectng the manifestation of genetic risk, contextual risk, and comorbid disorders such as childhood disruptive disorders (CDDs), influence both adolescent substance exposure and adult outcomes. Existing research has typically not accounted for such factors. Thus, even the few longitudinal studies that exist are limited in the inferences they permit. We propose extending a prospective study of 453 twin pairs, first assessed at age 11, to determine young adult outcomes at age 24. To increase the likelihood that misuse of substances would be widespread and to ensure sufficient representation of high-risk females, half of our community-based twin sample was enriched for the presence of CDDs; the other half was selected at random and is thus representative of twins born in Minnesota. Study participants completed a day-long in- person intake assessment that included substance use, mental health, overall adjustment, environmental risk and protective factors, electrophysiological measurement, academic achievement, and cognitive ability. Participants were re-assessed at age 14, when many were initiating substance use, and again at age 17, when substance misuse was becoming apparent. Our sample's current value derives from the wealth of data already gathered on the timing, duration, frequency, and intensity of exposure to specific substances coupled with our careful assessments of the twins' behavioral, environmental, and familial characteristics throughout adolescence. We will capitalize on the value of this sample by undertaking a comprehensive assessment of age-24 outcomes that broadly covers substance use disorders, mental health (including persistence of CDDs), and psychosocial, electrophysiological, and neuropsychological outcomes. A subsample of 216 twin pairs will also undergo an MRI assessment, adding to the uniqueness of our study. Our data analytic strategy emphasizes the innovative application of a co-twin differences design, a powerful method for clarifying effects due to substance use from those due to unmeasured confounding factors, including genetic factors. This novel approach capitalizes on the differences in the history of substance misuse that occur naturally within twin pairs as they grow up, allowing us to separate the effects of substance abuse from familial and psychosocial risk factors that predate substance exposure on their overall adjustment and brain functioning as adults. 1